Modification of expression of the malignant phenotype in radiation-initiated cells

Carcinogenesis is a multistage process consisting minimally of initiation and promotion/progression stages. Radiation and many environmental xenobiotics are potent initiating agents. We have shown that initiation of carcinogenesis in vivo by these agents is a common cellular event. In the irradiated thyroid (5 Gy) at least one in 20 cells is initiated. Initiation by both radiation and chemicals has also been shown to be a common cellular event in the mammary gland. Initiation therefore is most likely not the sole rate-limiting event in the carcinogenic process. The propensity of the initiated cell to express the malignant phenotype is modulated by many factors, including environmental chemicals and physiological and genetic factors. Scopal and abscopal physiological factors can either enhance or suppress the progression of initiated cells to a frank tumour. For example, prolactin enhances the rate of progression of radiation and chemically initiated mammary tumours while glucocorticoids suppress this progression. TSH enhances the progression of radiation-initiated thyroid tumours while a scopal factor associated with unirradiated thyroid cells suppresses progression of this tumour type.     

Sex differences in vasopressin neurons in the bed nucleus of the stria terminalis by in situ hybridization

To determine whether a sex difference exists in the biosynthetic capacity of vasopressingergic (AVP) neurons in the bed nucleus of the stria terminalis (BNST), we have used in situ hybridization and quantitative autoradiography to measure propressophysin messenger RNA levels in these cells from adult male and female rats. We have found that significantly more (p less than 0.01) neurons are labeled in male rats than in female rats and that these labeled cells averaged more grains/cell (p less than 0.05) in males than in females. Therefore, the sexual dimorphism of AVP pathways in the BNST and lateral septum recently shown by immunohistochemistry results from a sex difference in the biosynthetic capacity of these AVP neurons.     

High density lipoprotein particle size distribution in subjects with obstructive jaundice

High density lipoproteins (HDL) from 14 patients with obstructive jaundice were examined by gradient gel electrophoresis to determine the effect of obstruction on particle size distribution. HDL from 7 of these patients were fractionated by gel permeation chromatography and further characterized by electron microscopy, SDS gel electrophoresis, apolipoprotein A-I and apolipoprotein A-II immunoturbidimetry, and analysis of chemical composition. In addition, lecithin:cholesterol acyltransferase (LCAT) activity was measured and correlated with plasma apolipoprotein A-I concentration and particle size distribution. HDL were abnormal in all patients regardless of severity, cause, or duration of obstruction. The major HDL subfraction in normal subjects, HDL3a (radius 4.1-4.3 nm) was either absent or considerably diminished, and HDL2b (radius 5.3 nm) was also frequently absent. Very small particles comparable in size to normal HDL3c (radius 3.8 nm) were prominent. In patients with a bilirubin concentration greater than 250 mumol/l, normal HDL had totally disappeared and were replaced by large discoidal particles of radius 8.5 nm and small spherical particles of radius 3.6-3.7 nm. Both populations of particles were markedly depleted of cholesteryl ester and enriched in free cholesterol and phospholipid. The discoidal particles were rich in apolipoproteins E, A-I, A-II, and C, while the small spherical particles contained predominantly apolipoprotein A-I. LCAT activity was diminished in all subjects to 8-54% of normal, and was strongly positively correlated (r = 0.91 P less than 0.05) with plasma apolipoprotein A-I levels.     

Inhibition of liver prenyltransferase by citronellyl and geranyl phosphonate and phosphonylphosphate

Citronellyl- and geranylphosphonic acids and the corresponding phosphonylphosphates were made and tested as inhibitors of liver prenyltransferase. Kinetic analysis showed that citronellyl- and geranylphosphonylphosphate were powerful inhibitors of the enzyme, and that they were competitive inhibitors with geranyl diphosphate and noncompetitive inhibitors with isopentenyl diphosphate. Two inhibition constants, representing the equilibria [E][I]/[EI] = K5 and [ES1][I]/[ES1I] = K9, have been defined for the inhibitors. For citronellylphosphonylphosphate, the value of K5 was 1.25 microM and K9 was 3.30 microM; for geranylphosphonylphosphate, K5 = 1.50 microM and K9 = 1.60 microM. The phosphonates were very poor linear mixed noncompetitive inhibitors with respect to both substrates of the transferase.     

Abortion due to infection with Chlamydia psittaci in a sheep farmer's wife.

A farmer''s wife who had helped with lambing aborted spontaneously in March after a short febrile illness in the 28th week of her pregnancy. She developed disseminated intravascular coagulation post partum with acute renal failure and pulmonary oedema. Recovery was complete after two weeks of hospital care. A strain of Chlamydia psittaci, probably of ovine origin, was isolated from the placenta and fetus. The patient''s serum showed rising titres of antibody against chlamydia group antigen; the placental and fetal isolates; and a known ovine abortion, but not a known avian, strain of C psittaci. IgG against both ovine abortion and enteric strains of C psittaci was detected, but IgM against only an abortion strain was detected. Histological examination showed pronounced intervillus placentitis with chlamydial inclusions in the trophoblast but no evidence of fetal infection or amnionitis. Laboratory evidence of chlamydial infection was found in an aborting ewe on the farm in January and in remaining sheep and lambs in July. Doctors should recognise the possible risk to pregnant women in rural areas where chlamydial infections in farm animals are widespread.     

Radiogenic initiation of thyroid cancer: a common cellular event

A transplantation system for clonogenic cells in rat thyroid was used, which allows quantitative evaluation of both the acute cytotoxicity and the late neoplastic effects of ionizing radiation at the cellular level in vivo. We have obtained direct experimental evidence that radiogenic initiation of neoplasia in vivo is a common cellular event, and that cell number influences the expression of initiation. Ten per cent of those graft sites which had received 26 clonogens surviving 5 Gy developed carcinomas, while 4 per cent of those which received 26 unirradiated clonogens developed carcinomas. By comparison, 26 per cent of the sites that were inoculated with 411 surviving irradiated clonogens developed carcinomas while none of the 38 transplant sites that received 411 unirradiated clonogens developed carcinomas. Total tumour incidence (carcinomas plus adenomas) followed the same pattern.